This application is a renewal of an RO1 to understand the mechanisms by which EGF receptor family members are activated and signal. The family of receptors includes the EGF receptor itself, Neu, ErbB3 and ErbB4. It is noted in the application that ligand binding to a particular receptor induces or stabilizes homo- or heterodimer formation. The properties of the latter are especially interesting but not particularly well known. The initial emphasis of the proposal is on complexes established between the ErbB3 and Neu and the EGF receptor and Neu. The first aim deals with mechanisms of activation, and specifically how ErbB3, which is not an effective tyrosine kinase, promotes activation of Neu upon binding heregulin, and whether Neu is activated at all by the EGF receptor. The answers to both will be achieved by reconstitution of purified normal or mutant proteins in phospholipid vesicles. The second aim addresses proximal signaling molecules. One hypothesis is that tyrosine phosphorylation of ErbB3 by Neu accounts for binding of ErbB3 to p85. Also to be examined is the mechanism by which the EGF receptor achieves phosphorylation of the Cbl protooncogene. The third aim is to understand better pathways employed by the EGF receptor family further downstream. The potential for activation of the stress-activated MAP kinases will be examined, since some evidence exists for Cdc42 activation, and the identity of a novel GTP-binding protein activated by EGF and heregulin will also be explored. The GTP-binding protein is nuclear, binds RCC1, and is activated by UV light as well as growth factors.